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DOI: 10.1039/a908630g J. Chem. Soc., Perkin Trans. 1, 2000, 641–643 641

This journal is © The Royal Society of Chemistry 2000

Vinyl isonitriles in radical cascade reactions:formation of cyclopenta-fused pyridines and pyrazines

Isabelle Lenoir and Marie L. Smith*

The Centre for Chemical Synthesis, Department of Chemistry, Imperial College of Science,Technology and Medicine, London, UK SW7 2AY

Received (in Cambridge, UK) 29th October 1999, Accepted 18th January 2000

The 4 � 1 radical annulation reaction of vinyl isonitrileswith iodoalkynes or iodonitriles affording cyclopenta-fusedpyridines and pyrazines respectively and the first exampleof an intramolecular radical addition to an aryl isonitrileare described.

The application of tandem radical processes has proved to beboth an effective and efficient approach for the preparation of awide range of polycyclic molecules.1 Recently, isonitriles havebeen utilized in tandem radical processes for the formation of anumber of heterocyclic moieties.2,3 Precursors to the antitumoragent campthothecin and related natural products have beenprepared by such an approach.4 The 4 � 1 radical annulationstrategy adopted, involving intermolecular addition to the iso-nitrile and subsequent cyclisation, has, however, only beendescribed with aromatic isonitriles. Herein we describe ourefforts to further extend the scope of this methodology by util-izing vinylic isonitriles in place of aryl isonitriles as well asour initial investigations into the feasibility of tandem radicalreactions in which addition to an isonitrile occurs in the intra-molecular sense.

Four vinyl isonitriles 1a–d were chosen for our study andprepared via trifluoromethanesulfonic anhydride mediateddehydration of the corresponding vinyl formamides in reason-able yield (66, 87, 93, and 46% respectively).5 The vinyl form-amides may themselves be readily prepared according to themethods of Baldwin or Barton from the corresponding thio-oxime or oxime.6,7 Vinyl isonitriles 1a–d were treated with5-iodopentyne 2a at 150 �C and hexabutylditin (1.5 mmol) intert-butylbenzene under sunlamp irradiation for 48 hours.2,4 Ineach case a tetrasubstituted pyridine was obtained via thedesired 4 � 1 annulation (Scheme 1 and Table 1) in 46–72%yield. Unfortunately, despite extensive studies we were unableto significantly increase the yield of pyridine formation by vary-ing solvent (benzene, toluene), radical source (hexamethylditin)variation of reactant ratios, time and temperature. The form-ation of intractable material suggests isonitrile polymerisationis a competing pathway.

The likely mechanism for pyridine formation involves initialaddition of the alkyl radical 3 to the isonitrile carbon followedby 5-exo ring closure of the imidoyl radical 4 onto the alkyne toafford vinyl radical 5, Scheme 1. In theory radical 5 may cyclizeto either of two positions on the alkene, Scheme 1, via either a6-endo or 5-exo ring closure and thence to products 6 or 7. Witheach of the examples investigated only one pyridine productwas obtained. For isonitrile 1a (where R ≠ R1) with alkyne 2athe product was identified by X-ray analysis as 6a† rather thanthe alternative 7a thereby suggesting 6-endo closure as thepreferred route.

The scope of the methodology was expanded by the use of asubstituted iodoalkynes (namely 5-iodo-1-naphthylpent-1-yne(Scheme 1, Table 1)) with vinyl isonitriles 1a and 1b whichafforded the desired products albeit in moderate yield. Inaddition we have examined the use of iodonitrile 2c for theformation of a cyclopenta-fused pyrazine in an analogousmanner.3 Pyrazine 6g was obtained in 66% yield with isonitrile1a.

In an attempt to further the utility of isonitriles in radicalcascade processes we are currently investigating intramolecularradical addition to both vinyl and aryl isonitriles. Herein wereport the first example of intramolecular radical addition to anaryl isonitrile and the subsequent intermolecular trappingof the so formed imidoyl radical. Thus iodoisonitrile 8 wasprepared from 2,2�-dinitrobiphenyl. Treatment of 8 with tri-n-butyltin hydride–AIBN resulted in the formation of phen-anthridine 11 presumably via aryl and imidoyl radicals 9 and10. Treatment of 8 with electron rich alkenes such as tert-butyl vinyl ether with the slow addition of nBu3SnH–AIBNresulted in the formation of 15 although phenanthridine 11remained the major product. Not suprisingly this electron richalkene reacts more readily with the electron deficient imidoylradical than do more electron deficient alkenes and alkynes. Notrapping was observed with methyl propiolate and hex-1-eneunder identical conditions. Interestingly the use of a weakerhydrogen atom donor tris(trimethylsilyl)silane with tert-butylvinyl ether resulted in increased addition of the imidoyl radicalto the enol ether although we now obtained a new product 16which we believe to have resulted from rearrangement via 13and 14. The driving force for the rearrangement is, however, not

Scheme 1

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642 J. Chem. Soc., Perkin Trans. 1, 2000, 641–643

Table 1

Isonitrile Alkyne or nitrile Pyridine Yield (%)

Scheme 2

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J. Chem. Soc., Perkin Trans. 1, 2000, 641–643 643

immediately obvious (Scheme 2). The intramolecular additionto an aryl or vinyl isonitrile combined with intramoleculartrapping of the intermediate imidoyl radical is currently underinvestigation for the synthesis of biologically active naturalproducts.

Vinyl isonitriles have rarely been utilised in synthetic applica-tions.8,9 Herein we have demonstrated that vinyl isonitriles arereasonable substrates in 4 � 1 radical annulations with iodo-alkynes and iodonitriles for the formation of cyclopenta-fusedpyridines and pyrazines respectively. Both of these moietiesconstitute interesting pharmacophores for pharmaceuticals andagrochemicals. Finally we have shown that the intramolecularradical addition to isonitriles for the formation of 6-memberedrings is synthetically viable and our efforts to utilize thismethodology for the preparation of biologically active naturalproducts will be reported in due course.

Acknowledgements

We thank Professor A. G. M. Barrett for helpful discussions andsupport, the Royal Society for a Dorothy Hodgkin fellowship(to M. L. S.), Zeneca Agrochemicals for research funds and theWolfson Foundation for establishing the Wolfson Centre forOrganic Chemistry in Medical Science at Imperial College.

Notes and references† For 1c and 1d 1H and 13C NMR spectra suggested the product wasmost likely 6c and 6d respectively. For 1b it is not possible to distinguishbetween the pathways since R = R1. 6-endo Ring closure (or alter-natively a radical accelerated electrocyclisation reaction) forms six-membered ring product 18 which is then ultimately converted to prod-uct 6, path 2.‡ Pyridine 6 may also arise from 5-exo cyclisation of 5 to

form 17 followed by rearrangement, path 1c. Alternative product 7 mayarise from rearrangement of 17 to 22 via either 19, path 1a or 20, path1b. With each of the isonitriles 1a–d investigated only one pyridineproduct was obtained. The type of ring expansion depicted in paths 1band 1c is well precedented for simple β-multiply bonded alkyl rad-icals 2,10 but has rarely been observed for allyl or dienyl radicals.11 Foraryl isonitriles, at least, some experimental evidence exists to suggestthat path 1c is not operable12 and semiempiral calculations 3a suggest itis likely to be less favourable than a path 2 type process. We thereforebelieve that path 2 is likely to be the dominant pathway for the conver-sion of 1 to 6.‡ It is necessary to invoke an oxidation step to form 6 from 18. Theformation of aromatised products from dihydroaryl radicals underreductive conditions is not uncommon 13 but as with the aryl isonitrilesthe oxidant is not immediately obvious. Some evidence exists for theisonitrile itself acting as an oxidising agent.3a Should this be the case a

likely by-product with vinyl isonitriles would be the correspondingketone.§ However, we were unable to detect any ketone from reactionsof 1a–d. Other possibilities include radical disproportionation.2 Dis-proportionation of two molecules of 18 would give 6 plus a dihydro-pyridine moiety 23 which may be air-oxidised to 6 on work-up. On oneoccasion each with 6c and 6d we detected small amounts of a com-pound whose 1H NMR and mass spectra were consistent with a dihy-dropyridine moiety. Each compound was subsequently oxidised to thecorresponding pyridine on standing in air. It seems likely then thatradical disproportionation of 18 plays at least some part in the form-ation of 6 from 18.§ By analogy with the aryl isonitriles described in ref. 3(a) should vinylisonitrile act as oxidising agent it may be expected to lead to formationof a ketone as indicated in eqn. (1).

1 See for example: C. K. Sha, F. K. Lee and C. J. Chang, J. Am. Chem.Soc., 1999, 121, 9875; M. Kizil, B. Patro, O. Callaghan, J. A.Murphy, H. B. Hursthouse and D. Hibbs, J. Org. Chem., 1999, 64,7856; F. Belval, A. Fruchier, C. Chavis, J. L. Montero and M. Lucas,J. Chem. Soc., Perkin Trans. 1, 1999, 697; S. R. Baker, K. I. Burton,A. F. Parsons, J. F. Pons and M. Wilson, J. Chem. Soc., Perkin Trans.1, 1999, 427, S. A. Hitchcock, S. J. Houldsworth, G. Pattenden, D. C.Pryde and N. M. Thomson, J. Chem. Soc., Perkin Trans. 1., 1998,3181.

2 D. P. Curran and H. Liu, J. Am. Chem. Soc., 1991, 113, 2127; I. Ryu,N. Sonoda and D. P. Curran, Chem. Rev., 1996, 96, 177.

3 (a) C. M. Camaggi, R. Leardini, D. Nanni and G. Zanardi,Tetrahedron, 1998, 54, 5587; (b) D. Nanni, P. Pareschi, C. Rizzoli,P. Sgarabotto and A. Tundo, Tetrahedron, 1995, 51, 9045.

4 D. P. Curran, H. Liu, H. Josien and S.-B. Ko, Tetrahedron, 1996, 52,11385; H. Josien, D. Bom and D. P. Curran, Bioorg. Med. Chem.Lett., 1997, 24, 3189; H. Josien and D. P. Curran, Tetrahedron,1997, 53, 8881; D. P. Curran, H. Josien and S.-B. Ko, Angew. Chem.,Int. Ed. Engl., 1995, 34, 2683; D. P. Curran and H. Liu, J. Am. Chem.Soc., 1992, 114, 5863.

5 J. E. Baldwin and I. A. O’Neil, Synlett, 1990, 603.6 J. E. Baldwin, D. J. Aldous, C. Chan, L. M. Harwood, I. A. O’Neil

and J. M. Peach, Synlett, 1989, 9.7 D. H. R. Barton, T. Bowles, S. Husinec, J. E. Forbes, A. Llobera,

A. E. A. Porter and S. Z. Zard, Tetrahedron Lett., 1988, 29, 3343.8 For the application of vinyl isonitriles in Ugi 4-component

condensations see: T. A. Keating and R. W. Armstrong, J. Am.Chem. Soc., 1996, 118, 2574.

9 For the use of alkyl isonitriles in synthesis see: G. Stork and P. M.Sher, J. Am. Chem. Soc., 1983, 105, 6765.

10 P. Dowd and S.-C. Choi, Tetrahedron, 1989, 45, 77; A. L. J.Beckwith, D. M. O’Shea and S. W. Westwood, J. Am. Chem. Soc.,1988, 110, 2565.

11 M. Barbier, D. H. R. Barton, M. Devys and R. S. Topgi, J. Chem.Soc., Chem. Commun., 1984, 743.

12 R. Leardini, D. Nanni, G. F. Pedulli, A. Tundo and G. Zanardi,J. Chem. Soc., Perkin Trans. 1, 1986, 1591.

13 W. R. Bowman, H. Heaney and B. M. Jordan, Tetrahedron, 1991, 47,10119; D. Crich and J.-H. Hwang, J. Org. Chem., 1998, 63, 2765.

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